Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially fatal autoimmune blistering skin diseases in which autoantibodies against desmoglein 3 (Dsg3) and Dsg1, cell surface desmosomal adhesion molecules, cause loss of keratinocyte cell adhesion (Payne et al., 2004, Curr. Opin. Cell Biol. 16:536-543). PF is characterized by superficial blistering of only the skin, while PV typically presents with suprabasilar blistering of mucous membranes, which may extend to involve skin. ELISA studies have shown that all PF sera contain autoantibodies against Dsg1, and sera from patients with mucosal-dominant PV react mainly against Dsg3 (Ishii et al., 1997, J. Immunol. 159:2010-2017; Ding et al. 1997. J. Invest. Dermatol. 109:592-596; Amagai et al., 1999, J. Am. Acad. Dermatol. 40:167-170). PV patients who progress from mucosal to mucocutaneous lesions develop anti-Dsg1 in addition to anti-Dsg3 antibodies (Miyagawa et al., 1999, Br. J. Dermatol. 141:1084-1087). The anti-Dsg antibodies in pemphigus sera are pathogenic, since neonatal mouse passive transfer studies have shown that the extracellular domains of Dsg1 and Dsg3 can adsorb out pathogenic antibodies from PF and PV sera, respectively, and affinity-purified anti-Dsg1 or anti-Dsg3 antibodies cause characteristic disease (Amagai et al., 1994, J. Clin. Invest. 94:59-67; Amagai et al., 995, J. Invest. Dermatol. 104:895-901; Ding et al., 1999, J. Invest. Dermato, 112:739-743).
The autoantibody profile in pemphigus patients' sera, together with studies demonstrating the compensatory intercellular adhesive functions of Dsg1 and Dsg3 in normal epidermis (Wu, et al., 2000, N. Engl. J. Med. 343:31-35), accounts for the clinical and histologic sites of blister formation in pemphigus. In mucous membranes, Dsg1 is expressed predominantly in the superficial epithelium, while Dsg3 is expressed throughout (Shirakata et al., 1998, J. Invest. Dermatol., 110:76-78, Mahoney et al., 1999 J. Clin. Invest. 103:461-468). In skin, Dsg1 is expressed throughout the epidermis (predominantly superficially), while Dsg3 is expressed only in the basal and immediate suprabasal layers. Thus, consistent with the concept of “desmoglein compensation” (Wu et al., 2000, N. Engl. J. Med. 343:31-35), in PF, anti-Dsg1 antibodies cause blistering in the superficial epidermis, where Dsg1 but not Dsg3 is expressed, but they do not affect oral mucosa because of compensatory adhesion provided by Dsg3 throughout the epithelium. In mucosal PV, anti-Dsg3 antibodies cause blistering only in the basal layers of the mucosa, where Dsg3 is present without Dsg1 to compensate. The development of anti-Dsg1 in addition to anti-Dsg3 antibodies in mucocutaneous PV results in the extension of suprabasilar blistering to the epidermis.
Currently, therapy for PV is nonspecific and relies on general suppression of the immune system to ultimately lower antibody titers. To develop more targeted therapies for this disease, a finer understanding of both the T cell and the B cell immune response will be needed. A number of studies have examined the role of T lymphocytes in disease, through MHC-linked susceptibility, TCR gene usage patterns, the identification of T cell subsets contributing to disease, and the characterization of T regulatory cells in patients and MHC-matched controls (Wucherpfennig et al., 1995, Proc. Natl. Acad. Sci. U.S.A. 92:11935-11939; Hacker-Foegen et al., 2003, J. Invest. Dermatol., 121:1365-1372; Lin, et al., 1997, J. Clin. Invest. 99:31-40; Veldman et al., 2004, J. Immunol. 172:6468-6475; Nishifuji et al., 2000, J. Invest. Dermatol. 114:88-94).
Many more studies have focused on characterizing pemphigus autoantibodies. The relationship of the valence of autoantibodies to pathogenicity has been examined (Rock et al., 1990, J. Clin. Invest. 85:296-299; Mascaro, et al., 1997, Clin. Immunopathol., 85:90-96). Fab′ monovalent fragments, prepared by proteolytic degradation and alkylation/reduction of whole IgG from both PF and PV sera, cause histologically typical disease when passively transferred to neonatal mice. Furthermore, these monovalent antibody fragments may be more potent on a molar basis than bivalent IgG autoantibodies.
A number of anti-desmoglein antibodies have now been characterized and many of them do not appear to result in loss of keratinocyte adherence. Such human-derived, non-pathogenic antibodies may satisfy a need in the art for targeting molecules to specific tissues for the treatment of various non-pemphigus-associated conditions. The present invention meets these needs.